Peptide-based Inhibitors of Protein-Protein Interactions of Src Homology 2 Domain-Containing Phosphatase 2

Bobone, S.; Pannone, L.; Biondi, B.; Solman, M.; Flex, E.; Canale, V.; Calligari, P.; De Faveri, C.; Gandini, T.; Quercioli, A.; Torini, G.; Venditti, M.; Lauri, A.; Fasano, G.; Hoeksma, J.; Santucci, V.; Cattani, G.; Bocedi, A.; Carpentieri, G.; Tirelli, V.; Sanchez, M.; Peggion, C.; Formaggio, F.; Den Hertog, J.; Martinelli, S.; Bocchinfuso, G.; Tartaglia, M.; Stella, L.

doi:10.1101/2020.08.28.271809

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bioRxiv · 10.1101/2020.08.28.271809

Peptide-based Inhibitors of Protein-Protein Interactions of Src Homology 2 Domain-Containing Phosphatase 2

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Abstract

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in multiple signaling pathways and a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective on disease-associated SHP2 mutants. Based on the consideration that pathogenic lesions cause signaling hyperactivation due to increased SHP2 association with cognate proteins, we developed peptide-based molecules with low nM affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation and an affinity for pathogenic variants of SHP2 up to 20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2.

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Bobone, S., Pannone, L., Biondi, B., Solman, M., Flex, E., Canale, V., Calligari, P., De Faveri, C., Gandini, T., Quercioli, A., Torini, G., Venditti, M., Lauri, A., Fasano, G., Hoeksma, J., Santucci, V., Cattani, G., Bocedi, A., Carpentieri, G., Tirelli, V., Sanchez, M., Peggion, C., Formaggio, F., Den Hertog, J., Martinelli, S., Bocchinfuso, G., Tartaglia, M., Stella, L.. 2020-08-28. Peptide-based Inhibitors of Protein-Protein Interactions of Src Homology 2 Domain-Containing Phosphatase 2. https://doi.org/10.1101/2020.08.28.271809

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